Lewis acid-mediated transformations of 5-acyl-N-fluoroalkyl-1,2,3-triazoles to cyclopentenones, indenones, or oxazoles

We present a transition metal-free approach to 2-N-substituted indenones, cyclopentenones, and 4-carbonyl oxazoles, based on the reaction of 5-acylated N-fluoroalkyl substituted 1,2,3-triazoles (prepared by a three-component click reaction of copper acetylides, fluoroalkyl azides, and acyl chlorides) with Lewis acids aluminium trichloride or boron trifluoride etherate, proceeding via the generation and cyclization of vinyl cations.


Introduction
2][3][4][5][6] Synthetic strategies for obtaining their N-alkenyl derivatives (2-Nsubstituted cyclopentenones and indenones) or fully substituted oxazoles are limited because of the low availability of the starting materials and the necessity to use transition metal complexes or harsh reaction conditions.There is no general synthetic approach leading to these structures and each type of product requires a specic methodology.Despite the availability of numerous synthetic methods for the preparation of mono-or di-substituted oxazoles, 7 access to tri-substituted 4-carbonyl oxazoles is not well explored and relies mainly on the intramolecular Cu-catalyzed cyclization of (thio)enamides 8 or bromo(thio) enones, 9 or on a protocol starting from 2-azido enones 10 or alkynyl ketones. 11-N-substituted indenones can be accessed from ynamides, 12 2-alkynylbenzoyl cyanides, 13 or 2-hydroxy-substituted internal alkynes.14 2-Amino indenones were also prepared via Aucatalyzed intermolecular oxidation of 2-carbonyl-1-ethynyl benzenes 15 or by co-catalyzed annulation of thioamides with ynamides.16 Approaches leading to 2-amino-substituted cyclopentenones are limited to methods starting from previously modied cyclopentenone or cyclopentane rings.[17][18][19] Other procedures, starting from ynamides, 20 a-aminoenals 21 or vinyl ketenes, 22 are highly substrate-specic and do not allow for the further modication of the amino position in cyclopentenones.

Results and discussion
Synthesis of 5-acetyl-and 5-benzoyl-substituted 1,2,3-triazoles by an intercepted click reaction was briey described in the literature. 31For our study it was necessary to prepare a library of 1-(per)uoroalkyl-4-substituted-5-acyl-1,2,3-triazoles.However, application of Wu's conditions 31 (phenylacetylene, CuI, Et 3 N and benzoyl chloride or acetyl chloride) with our uorinated azides 23,32,33 (CF 3 N 3 or C 2 F 5 N 3 ) did not afford the desired 5acylated triazoles.Therefore, we turned to the use of (phenylethynyl)copper (1a), which was shown to be reactive with azido(per)uoroalkanes in intercepted click iodination or allylation. 28A three-component reaction of 1a, azidopenta-uoroethane (2a) and methacryloyl chloride was used for the optimization of the synthesis of triazole 3a (Table 1).Initially, a mixture of 3a and triazole side-product 3a-H formed (entry 1).Increasing the amount of acyl chloride and using anhydrous conditions improved the yield of 3a and suppressed the formation of 3a-H (entries 2-4).To further increase the yield of 3a, screening for an additional base was conducted (entries 5-11), identifying DIPEA as the most efficient one (entry 12).Finally, the use of 2 equiv. of acyl chloride and 3 equiv.of DIPEA provided 3a in optimized yield (entry 14).
Having established the optimal reaction conditions for the intercepted click reaction and acylation sequence, the scope of the protocol was investigated on diverse acetylenic substrates, uorinated azides, and acid chlorides (Scheme 3).5-Methacryloyl triazoles (3b-e) with strongly electron-poor or electronrich aryl rings in position 4 were prepared in moderate yields.To demonstrate the scalability of reaction, triazole 3a was prepared on 1.76 g (10.7 mmol) scale in high yield.5-Benzoylsubstituted triazoles (3f-i) were also prepared in good yields.Varying the azide reagent revealed that highly uorinated azidoalkanes afforded better product yields than tosyl azide or ethyl azidodiuoroacetate.Modication of triazoles in position 4 with aryl, alkyl and alkenyl groups and modication in position 5 with aryl, heteroaryl, alkyl, cycloalkyl and alkenyl groups afforded products mostly in satisfactory yields.Scale-up of 3f and 3y to 4-5 mmol was also successful.
Next, AlCl 3 was chosen as a suitably strong and easily available Lewis acid to investigate the denitrogenative transformation of 5-acryloyl substituted triazoles.Cyclization of the formed vinyl cation intermediate onto the alkene moiety and chloride capture of the resulting carbocation led to the formation of cyclopentenone imidoyl chlorides (4a-d) in moderate yields (Scheme 4).The cation-stabilizing p-methoxyphenyl group in position 4 of triazole 3 improved the product yields.This observation, together with the necessity of triazole denitrogenation in the initial step of the reaction, speaks against an alternative reaction mechanism involving Nazarov cyclization, typically starting from a divinyl ketone.BF 3 $OEt 2 was used for the preparation of uorinated cyclopentenone amides 4e-g from triazoles 3 (Scheme 4).In the case of N-CF 3 triazole 3j, the nal product is not a cyclopentenone amide but cyclopentenone isocyanate 4h due to the facile HF elimination of the NHC(O)F intermediate.Triazole 3r was a special case, as the vinyl cation intermediate induced a 1,5-hydride shi to form a tertiary carbocation and an a,b-unsaturated ketone.Cyclization and proton elimination afforded cyclopentenone 4i (Scheme S1 in the ESI †).
Subjecting 5-benzoyl triazoles 3 to a reaction with AlCl 3 led to the cyclization on the aryl ring of the benzoyl moiety, forming indenone imidoyl chlorides 5 (Scheme 5).Again, the presence of vinyl cation-stabilizing groups in position 4 of the starting triazole and electron-rich groups on the aryl ring of the substituted benzoyl moiety in position 5 of the triazole both increased product yields.Using 5-benzoyl triazoles instead of dimethoxybenzoyl triazoles afforded only low to moderate indenone yields.
The formation of 4-acyl oxazoles 6a-g was observed upon boron triuoride-mediated transformation of 5-benzoyl triazoles (Scheme 6).Two isomers of products 6 can be formed: electron-rich or -neutral aryl groups in position 5 of the starting triazole cyclized selectively to form isomer A and triazoles with deactivated aryl groups in position 5 gave a mixture of isomers A and B with good to high selectivity for isomer A. Heating the mixture of isomers in a microwave did not lead to their interconversion, ruling out the possibility of Cornforth rearrangement in 2-triuoromethyloxazoles.Oxazole 6f was accompanied by indenone 5f side-product.Oxazolone 6g was prepared selectively from 3m, as 2-uorooxazoles are hydrolytically unstable.
To rationalize the formation of products 6A and 6B, we considered the following reaction mechanism (Scheme 7).As demonstrated in our earlier report, 27 the coordination of BF 3 to nitrogen atoms of the triazole ring (particularly the coordination to N1) led to opening of the triazole ring and the The synthetic utility of cyclopentenone imidoyl chlorides was demonstrated on examples of post-functionalization of 4a (Scheme 8).Triuoromethylated tetrazole 7a was easily prepared from 4a using sodium azide.The addition of an aqueous ammonia solution afforded amidine 7b, and the addition of aqueous hydrazine led to the cyclization of the carbonyl and imidoyl chloride functional groups to give tri-uoromethylated triazine 7c.We proposed that 7c is formed by cyclization of hydrazine nitrogen to the six-membered ring,

Conclusions
In conclusion, we present the synthesis of N-electron-acceptor group-substituted 5-acyl-1,2,3-triazoles by an intercepted click reaction, namely a three-component cyclization of azide, copper acetylide and acyl chloride.Lewis acid-mediated triazole ring opening and nitrogen molecule elimination provided key reactive intermediatesvinyl cations, which cyclized selectively to form either cyclopentenone imidoyl chlorides, indenone imidoyl chlorides, cyclopentenone amides, or 2-triuoromethyl oxazoles, depending on the combination of the Lewis acid used and the substitution in position 5 of the triazole ring.Postfunctionalization of cyclopentenone imidoyl chloride gave access to selectively functionalized N-alkenyl compounds (amidines) or new nitrogen heterocycles (triazine or tetrazole).
The presented methodology demonstrates a Lewis acidmediated generation of vinyl cations from triazoles and their synthetic utilization in the formation of new C-C bonds.